Abstract
The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.
Highlights
Introduction and OverviewBricks and Mortar: Which Matters More?Amniotes have acquired a specialized barrier function in the stratified squamous epithelia to cope with harsh terrestrial conditions [1]
The stratum corneum (SC) endows the epidermis with impermeability above the tight junction (TJ) [2] and serves as mechanical insulation, taking advantage of the durability and resiliency of the cornified cell envelopes (CE) [3]. These structural and functional analogies allow us to compare the SC to bricks and mortar [4]; bricks correspond to corneocytes, and mortar denotes lipid bilayers provided from the lamellar granule (LG) secretory system located in the stratum granulosum (SG)
Because submerged keratinocyte culture is not a suitable experimental setting to understand the function of LOR for the reasons mentioned above [15,16,18,20], a rodent model is ideal to determine the consequence of the loss or dysfunction of the major CE protein
Summary
Amniotes have acquired a specialized barrier function in the stratified squamous epithelia to cope with harsh terrestrial conditions [1]. Loss-of-function (LOF) in LG lipid transporter ATP binding cassette subfamily A member 12 (ABCA12) results in ARCI4B (harlequin ichthyosis, OMIM #2425500), while that in transglutaminase 1 (TGM1) impairs corneocyte lipid envelope formation [3] and causes ARCI1 (lamellar ichthyosis (LI), OMIM #242300) [5] These lines of evidence unequivocally suggest the instrumental roles of the “mortar” (the paracellular lipid) in the maintenance of skin barrier homeostasis, and a universal clinical phenotype is a reactive hyperkeratosis. There are the complexity and redundancy regarding the consequence the defects in CE, the “brick”; genetic deletion of either major CE precursors, involucrin (IVL) [6], or loricrin (LOR) [7], do not produce conspicuous phenotypes in mice, and human pathological counterparts have not yet been reported This may be because the epidermal differentiation complex (EDC) constitutes a diversified family [8,9] and facilitates compensation for the loss of the major CE constituents [7,10,11]. This review aims to clarify the functional significance of a major CE protein LOR from a biochemical, pathological, or immunological aspect with some theoretical perspectives
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